Treatment of
Monogenic Diseases

Gene therapy is a promising approach
for both monogenic and complex diseases.

Monogenic Diseases

Monogenic diseases are genetic disorders caused by modifications in a single gene occurring in all cells of the body1

Examples include spinal muscular atrophy and inherited retinal disease2

Complex Diseases

Other diseases have more complex roots, involving multiple genetic abnormalities in conjunction with other factors1

Examples include cancer and heart failure1

Monogenic Diseases: Single Gene Mutation Disease

Alterations within a single gene occurring in all cells of the body are sufficient to cause a monogenic disorder3

The manifestation of the genetic disease depends on the functions associated with the protein processed from the altered gene3

More than 10,000 human genetic diseases are monogenic3


Classifications of Monogenic Diseases

The inheritance pattern of nuclear monogenic diseases can be classified into three main categories1,2




A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease1

Dominant mutations often lead to a gain of function, but may also be associated with a loss of function, or have a dominant-negative effect2*


Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype1,2

Recessive mutations inactivate the affected gene and lead to a loss of function2


In females, a mutation in one of the two copies of the gene on either of the two X chromosomes is sufficient to cause an X-linked dominant disorder; in males, a mutation in the only copy of the gene on the single X chromosome causes the disorder1

Males are usually more severely affected than 
female heterozygotes because they carry only 
one X chromosome1,2


Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder1

In males who have only one X chromosome, a mutation in the only copy of the gene is sufficient to cause the disorder; in females who have two X chromosomes, a mutation needs to occur in both copies of the gene to cause the disorder1

Because it is unlikely that females will have two 
altered copies of the gene, males are more 
frequently affected than females1

Inheritance Patterns4,5

Autosomal Dominant
Autosomal Recessive
X-Linked Dominant
X-Linked Recessive


Huntington disease:
Gain-of-function mutation in the HTT gene

Marfan Syndrome:
Evidence for haploinsufficiency† or 
dominant-negative effect of the FBN1 gene


Cystic Fibrosis:
Loss-of-function mutations in the CFTR gene

Spinal Musclular Atrophy:
Bi-allelic deletion or mutation in the SMN1 gene, which leads to insufficient SMN protein


Rett syndrome:
Loss-of-function mutations in the MECP2 gene


Loss-of-function mutations in the F8 or F9 gene*

Fabry disease:
Loss-of-function mutations in the GLA gene

Examples of Monogenic Diseases for Which Gene Therapy Approaches Are Being Studied

Blood Disorders

(i.e. thalassemias, sickle cell2,3)


Pulmonary Disorders

(e.g. cystic fibrosis2,3)


Neurodegenerative Disease

(e.g. Batten disease,2,4
spinal muscular atrophy,5 SOD1 mutations in ALS6)


Neurologic Disorders

(e.g. Rett syndrome7)

  1. Wang D, Gau G. Discov Med 2014;18:151–161.
  2. Ginn SL, et al. J Gene Med 2018;20(5):e3015.
  3. World Health Organization. Genes and human disease. Available at: Accessed January 29, 2019.
  4. Worku D. Intern Med 2017;7:6.
  5. Prior TW. Genet Med >2010;12(3):145–152.
  6. Bosco DA. Nature Education 2015;8(3):4. Available at: Accessed December 6, 2018.
  7. Liyanage VRB, Rastegar M. Neuromolecular Med 2014;16(2):231–264.
  8. NIH. How does gene therapy work? Available at: Accessed January 29, 2019.
  9. Gambello MJ, Li H. J Genet Genomics2018;45(2):61–70.